Targeting prostate cancer with gold nanoparticles
A project by: Jonathan Coulter
About the project
Prostate Cancer UK has funded us to develop a novel gold nanoparticle, which increases the sensitivity of tumour cells to radiotherapy. We plan to slightly adapt the surface of our nanoparticle to specifically target and kill prostate cancer stem cells; the cells thought to be primarily responsible for treatment failure.
Why is research needed in this area?
The goal of this research is to generate preliminary evidence that this nanoparticle configuration could improve the radio-curability of advanced localised prostate cancer.
Treatment resistant, cancer stem cells are thought to be a major contributor to tumour recurrence. Radiotherapy represents the most significant curative treatment modality for prostate cancer while the disease remains localised. However, almost 30% of patients with locally advanced prostate cancer will develop progressive disease with limited treatment options. The work proposed here will “add value” to our current Prostate Cancer UK project where we are constructing a novel gold nanoparticle designed to preferentially increase radiation induced damage to the cell plasma membrane. Using the core from this nanoparticle we will substitute the surface functional group with an FKBPL-based therapeutic peptide which has both anti-angiogenic/anti-stem cell properties. The clinical candidate, ALM201, is currently in a PhaseI/II clinical trial for the treatment of ovarian cancer. The peptide targets CSCs and promotes differentiation towards a more treatment sensitive phenotype. Furthermore, the anti-angiogenic properties of the peptide along with the radio-sensitising properties of the gold nanoparticle could significantly boost the efficacy of each component.
Significance of this project
To date, individual components (i.e. the gold nanoparticle and our targeting peptide) have demonstrated significant efficacy as a potent radiosensitiser and anti-stem cell therapeutic, respectively. In the in vitro setting, we anticipate that this novel nano-conjugate will preferentially target cancer stem cells, thereby reducing or eliminating clonogens responsible for treatment failure.
We have preliminary evidence indicating that radiation treatment alone may worryingly elevate the proportion of cancer stem cells, but that this peptide can abrogate this effect. This evidence provides a solid basis for widening the scope of our research in order to establish the anti-cancer stem cell effect in a variety of prostate cancer models.
Importantly, the conjugation of an FKBPL-based peptide to a gold nanoparticle will confer additional favourable properties. In the first instance the nanoparticle will improve delivery of peptide to the tumour over free peptide, due in part to the irregular vasculature of the tumour, thereby promoting accumulation within the tumour interstitium. Secondly, radiation/gold interactions markedly increase the radiosensitivity of gold-doped cells, providing a novel strategy for overcoming the inherent radioresistance observed in these low-frequency sub-populations. We anticipate that this strategy could eventually significantly increase the radiocurability of advanced localised prostate cancer.
Goals of the projecT
1. To develop and assess the physical characteristics of the gold nanoparticle conjugate
2. To establish if conjugated peptide retains the functionality of the free peptide; various modifications of the peptide will be necessary
3. To determine if both components (gold nanoparticle and peptide) are more effective than the sum of their individual parts, when combined with radiation
4. Enrich for cancer stem cell populations and establish the efficacy of the nanoparticle in reducing treatment resistant sub-populations